HOST

W. Frank “Peek-a-Boo” Peacock IV, MD

Vice Chief of ResearchDepartment of Emergency Medicine

The Cleveland ClinicCleveland, OH

Debate Format

• Introduction from moderator

• 7 minute presentation from each side of the debate

• 2 minutes rebuttal from each side

• 4 minutes for questions from the audience

Questions from the Audience

• 4 minutes for questions

• Question cards were given to you during registration and will be collected during and after the debate

• May also use floor microphones

Registration

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Pro: “Cleveland Assassin

Emerman”

Vasoactive Agents in ADHF

Con: “Southpaw Storrow”

Charles L. “Cleveland Assassin”

Emerman, MD

BADASS

Vasoactive Agentsin Heart Failure:

You Aren’t Going to Use These?

Charles L. Emerman, MD

Professor and Chairman of Emergency Medicine

Case Western Reserve University

My Opponent: Dr. Storrow

Perhaps He’d Like You to Use…

Or, Perhaps He’d Like Us to Use…

We Aren’t Talking About Vasoconstrictors / Inotropes Here

Cuffe MS, et al. JAMA. 2002;287:1541–1547.

Ev

ent

Ra

te (

%)

Treatment Failure From Adverse

Event (48 h)

Sustained Hypotension

Acute MyocardiaI Infarction

Mortality

MilrinoneMilrinone

PlaceboPlacebo

Atrial Fibrillation

P < 0.001 P < 0.001

P = 0.18

P = 0.004P = 0.19

12.6

2.1

10.7

3.21.5

0.4

4.6

1.5

3.82.3

0

5

10

15

20

OPTIME-CHF: In-hospital Adverse Events

Dobutamine (n = 141)

Nes 0.015 g/kg/min (n = 187)

Cu

mu

lati

ve M

ort

alit

y R

ate

(%)

Time From Start of Treatment (days)

Nes 0.030 g/kg/min (n = 179)

Effect of Short-term Nesiritide or Dobutamine on 6-Month Survival

05

10

15

20

25

30

35

0 30 60 90 120 150 180

Log-rank test:Dobutamine vs nesiritide 0.015 g/kg/min P = 0.041Dobutamine vs nesiritide 0.030 g/kg/min P = 0.445Nes 0.015 g/kg/min vs nes 0.030 g/kg/min P = 0.187

Elkayam U, et al. J Cardiac Fail. 2000;6(Suppl 2):169.

But If You Add Vasodilators to Inotropes, You Improve Your Results

The Debate Here Isn’t Between NTG and Nesiritide: It is Vasodilators Versus Usual Care with Diuretics

Ch

ange

fro

m B

asel

ine

in P

CW

P (

mm

Hg)

End of Placebo-Controlled Period

Time on Study Drug (Hours)

During 3-hour Placebo PeriodPlacebo, n = 62 IV NTG, n = 60Nesiritide, n = 124

After 3-hour PeriodIV NTG, n = 92Nesiritide, n = 154

†P < 0.05 vs IV NTG*P < 0.05 vs placebo

*

†*

0 0.25 0.5 1 2 3 6 9 12 24 36 48

-9

-8

-7

-6

-5

-4

-3

-2

-1

0PCWP - Placebo

PCWP - IV NTG

PCWP - Nesiritide

†*

†* †

** †

* †

†††

*

NTG, nitroglycerin; PCWP, pulmonary capillary wedge pressure; IV, intravenous.

Effects of Non-PSDs

Favors Non-PSD

HF hospitalization

Cardiovascular death

Arrhythmic death

Any death

Adverse Effect of Non-PSD

0 1 2Hazard Ratio

Data from the SOLVD trial.J Am Coll Cardiol. 2003;42:705––708. Circulation. 1999;100:1311––

1315.

PSD, potassium-sparing diuretic; HF, heart failure.

Nesiritide Blocks Adverse Actions of Furosemide

• Experimental study of paced induced HF in dogs

• Nesiritide improved urine sodium excretion, glomerular filtration rate (GFR), and urinary output

Circulation. 2004;109:1680––1685.

The More You Use,the More You Lose

• 1,354 patients divided into furosemide dose quartiles

• Highest quartile had lowest ejection fraction, sodium level, and hemoglobin level and highest creatinine (Cr)and blood urea nitrogen (BUN) levels

• Even after adjustment, significant difference in outcome

Am J Cardiol. 2006;97:1759––1764.

Chronic Diuretic Use and Hospital Mortality

0

1

2

3

4

5

6

7

8

Mortality

Nodiuretics

Diuretics

Nodiuretics

Diuretics

• Data from 45,000 in the ADHERE registry

• Effect of diuretics in past 90 days

• Also found increase in length of stay (LOS)

• Patients previously on diuretics less likely to be discharged to home asymptomatic

Costanza MR. 2004 ACC meeting.CR <2 CR >2

Impairment in Renal Function

• Administration of furosemide associated with drop in GFR and plasma flow and rise in mean arterial pressure

• Effect blunted by losartan

Chen HH. Am J Physiol Renal Physiol. 2003;284:F1115––F1119.

High-Dose vs Low-Dose Diuretics and Vasodilators

• 110 patients with acute decompensated heart failure (ADHF)

• Randomized to low-dose furosemide + high-dose IV NTG or repeated high doses of furosemide and low dose of IV NTG

• More rapid improvement of pulse oximetry in group A

0%

5%

10%

15%

20%

25%

30%

35%

40%

A B

Intubate

Any AE

Lancet. 1998;351:9100.

In Other Words:Vasodilators — GoodDiuretics — Not So Good

                              

Alan B. “Southpaw” Storrow, MD

Nitro Is Being Bullied…and you should be mad about it

Alan B. Storrow, MD

Vice Chairman for Research

Department of Emergency Medicine

Vanderbilt University

The Life Story of “Nitro”

• NTG grew up poor– (i.e. no industry backing)

• Worked hard and worked well, despite growing up around the stuck-up rich kids – (milrinone, nesiritide, levosimendan)

• Remains a hard-working blue collarHF drug

NTG in a Nutshell

• Low dose: venous vasodilation

• High dose: arterial vasodilation

• Vasodilatation leads to decreased PCWP, preload and afterload

• Improves epicardial coronary blood flow and CO

• Little or no change in heart rate

NTG Studies in ADHF

Does it work?

Sublingual NTG in ADHF

• Hemodynamic effects• Sublingual captopril vs NTG in ADHF• 24 ICU patients: PCWP >20 mm Hg and CI <2.5 L/min/m2

• Baseline diuretics and digoxin: no inotropes/vasodilators• Systolic blood pressure 110–130 mm Hg• Randomized to either

– Captopril 25 mg sublingual (pill chewed)– NTG 0.8 mg sublingual

Haude M, et al. Int J Cardiol. 1990;27:351–359.

Does Topical NTG Work in ADHF?

• The “chili dog” effect

• Application of NTG paste to 13 patients with PCWP >18 mm Hg

• 2.5–5 cm of NTG paste

• Hemodynamic response over 6 hours

Kawai C, et al. Clin Ther. 1984;6:677–688.

Before NTG

After NTG

PCWP(mm Hg)

26.3 16.8*

CI(L/min/m2)

2.7 2.9

SVR(dynes.s/cm-5)

1,920 1,520*

*P < 0.005.*P < 0.005.

SVR, systemic vascular resistance.

High-Dose IV NTG in ADHF• 104 patients with ADHF

– Chest x-ray + O2 saturation <90%, blood pressure >110/70 mm Hg

• Randomized to– A: 3 mg isosorbide dinitrate IV q 5 minutes + furosemide 40 mg IV– B: isosorbide dinitrate 1 mg/h (titrated 1mg/h every 10 minutes) +

furosemide 80 mg IV every 15 minutes• Continued until

– O2 saturation >96%

– Mean arterial pressure decreased 30% or to <90 mm Hg• Primary end point

– In-hospital death– Intubation within 12 hours (criteria)– Acute myocardial infarction within 24 hours

Cotter G, et al. Lancet. 1998;351:389–393.

High-Dose IV NTG in AHF

Cotter G, et al. Lancet. 1998;351:389–393.

P = 0.006P = 0.006

High-Dose IV NTG in AHF

Cotter G, et al. Lancet. 1998;351:389–393.

Conclusion: High-dose NTG after low-dose furosemideis safe and effective in controlling pulmonary edemaConclusion: High-dose NTG after low-dose furosemideis safe and effective in controlling pulmonary edema

• Retrospective analysis of ADHERE• Comparison of >15,000 patients who received IV

– NTG– Nesiritide– Dobutamine– Milrinone

• 1st - univariable predictors of mortality• 2nd - propensity scores for each • 3rd - logistic regression to predict mortality adjusting

for steps 1 and 2

Is Little NTG Colicky(Nitrate Tolerance)?

• Theoretical decreased hemodynamic and clinical effect after prolonged use of NTG

• *Three possible mechanisms: – 1) Plasma volume expansion– 2) Neurohormonal – 3) Free radicals

• Conflicting data except free radical idea: supported well in rats and isolated blood vessels

* Elkayam O. J Cardiol Pharm Ther. 2004;9:227–241.

Colic, or Just Gas?

• Tolerance prevention – 12 hours on and 12 hours off– Oral hydralazine

• Take-home point: in the first 6–12 hours, with aggressive up-titration — not an issue — VMAC an example

Guidelines for Little NTG

• American College of Cardiology/American Heart Association (ACC/AHA): Helpful for chronic heart failure — nothing about acute

• European Society of Cardiology (ESC): Helpful in ADHF — Class I, level B evidence

• Heart Failure Society of America (HFSA): NTG used to improve congestion in those patients not hypotensive — Strength = C

• American College of Emergency Physicians (ACEP): Level B — “administer IV nitrates to patients with acute heart failure and dyspnea”

VMAC: A Closer Look at the Data

• NTG was NOT titrated aggressively

• Mean dose of NTG at 3 hours in catheterized and noncatheterized?

• 42 and 29 mcg/min

Result of Poor Titration

Placebo

Nesiritide

NitroChanges from baselinein PCWPChanges from baselinein PCWP

Publication Committee for the VMAC Investigators. JAMA. 2002;287:1531–1540.

Publication Committee for the VMAC Investigators. JAMA. 2002;287:1531–1540.

Outcomes at 3 and 24 Hours for All Treated Patients by Randomization Group

“High-Dose NTG” Subgroup

• Subgroup comparison of patients who received high-dose NTG (n = 12) and nesiritide (n = 15)at one center

• Maximum mean dose of NTG was 161 mcg/min

• Maximum mean infusion of nesiritide was0.012 mcg/kg/min

Elkayam U, et al. Am J Cardiol. 2004;93:237–240.

“High-Dose NTG” Subgroup

“High-Dose NTG” Subgroup

2007 High-DoseOutcome Analysis

• Nonrandomized• 29 hypertensive,

refractory patients• 2-mg boluses every

3 minutes up to10 doses

• Mean = 6.5 mg• Compared with non–

high-dose group

• Less intubation– 14% vs 27%

• Less bilevel positive airway pressure– 7% vs 20%

• Less ICU admission– 37% vs 80%

• Adverse events uncommon

Levy P. Ann Emerg Med. 2007;50:144–152.

As If I Really Need One

Dr. Storrow

Predictors of Worsening Renal Function

Butler J, et al. Am Heart J. 2004;147:331––338.OR, odds ratio; CI, confidence interval.

Impact of Diuretic Dosing on Outcomes in Decompensated HF

• Data derived from ADHERE database • ~80,000 patients who received

diuretics but no inotropes or vasodilators

• Divided patients based on diuretic dose in first 24 hours <160 mg vs 160 mg

J Cardiac Fail. 2004;10:S114––S368.

Groups Reasonably Matched for Concomitant Medications

Medications Dose <160 mg(%)

Dose 160mg (%)

ß-blockers 38,370 (61.0) 12,049 (61.2)

ACE inhibitors 36,771 (58.5) 10,971 (55.8)‡

ARBs 8,760 (13.9) 3,012 (15.3)‡

Calcium channel blocker

16,009 (25.5) 5,408 (27.5)‡

Peripheral vasodilator

3,359 (5.3) 1,695 (8.6)‡

J Cardiac Fail. 2004;10:S114––S368.

‡‡P P < 0.05.< 0.05.

ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker.

Prior Medications

Dose <160 mg (%) Dose 160 mg (%)

Diuretics 67.1 82.3‡

ß-blockers 47.6 50.7‡

ACE inhibitors 39.8 41.8‡

ARBs 11.9 13.3‡

J Cardiac Fail. 2004;10:S114––S368.‡P < 0.05.

Laboratory DataDose <160 mg Dose 160 mg

Elevated troponin (μg/L)

5.2 5.7‡

BNP, median (pg/mL)

704 782‡

Cr (mg/dL) 1.2 1.4‡

LVEF <40% 44.7 46.9‡

BUN, median (mg/dL)

16.0 18.0‡

J Cardiac Fail. 2004;10:S114––S368.

‡P < 0.05.

BNP, B-type natriuretic peptide; LVEF, left ventricular ejection fraction.

Renal Outcomes

0

5

10

15

20

25

30

? Cr>.5 Newdialysis

<160 mg

=>160 mg

J Cardiac Fail. 2004;10:S114––S368.

Clinical Outcomes

0123456789

10

Mortality ICU admit Hosp LOS

<160 mg

=>160 mg

J Cardiac Fail. 2004;10:S114––S368.

Multivariate Adjusted Results

J Cardiac Fail. 2004;10:S114––S368.ICU, intensive care unit.

In-hospital MortalityICU AdmissionsLength of Stay Total > 4 days ICU > 3 daysRenal Function SCr increase > 0.5 mg/dl ≥ 10 mL/min decrease in GFR Initiation of dialysis

Adjusted Odds Ratio (95% CI) P-value

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

High Dose vs Low-Moderate Dose IV DiureticBetter Worse

You Don’t Want This Unhappy Kidney, Do You?

Of Course Not – You WantMr. Happy Kidney

Nesiritide: Another Trust Fund Kid?

Guideline Recommendations for Nesiritide

• ACC/AHA: No comment on ADHF• HFSA: In the absence of hypotension,

nesiritide (or NTG) can be considered as an addition to diuretics for improvement in congestion (Strength = C)

• ESC: Discuss its potential use, but no recommendation

• ACEP:

A Visionary?

Is Chuck Really Harry?

0 30 60 90 120 150 1800

10

20

30

40

50

60

70

80

90

100

Time Observed from the Start of Treatment (days)

NTG (n = 216)

Nesiritide 0.01 µg/kg/min (n = 211)

All nesiritide (n = 273)

Stratified log-rank test:

NTG vs nesiritide 0.01 µg/kg/min P = 0.616

NTG vs all nesiritide doses P = 0.319

Mortality Rates: VMAC Over 6 MonthsC

um

ula

tive

Mo

rtal

ity

Rat

e (%

)

Young JB, et al. AHA Meeting 2000 Late Breaking Trials Session.

Circulation Meta-analysis

• Pooled analysis of 5 trials– VMAC, PRECEDENT, Mills, Colucci x 2

• Relative risk = 1.52 (1.16–2.00) for worsening renal function

• Relative risk = 2.29 (1.07–4.89) forrenal failure

• No difference in need for dialysis

Sackner-Bernstein JD, et al. Circulation. 2005;111:1487–1491.

JAMA Meta-analysis• 3 trials pooled

– NSGET, VMAC, PROACTION

• Relative risk of death at 30 days for those on nesiritide = 1.74 (0.97–3.12)

Sackner-Bernstein JD, et al. JAMA 2005;293:1900–1905.

Food and Drug Administration Interim Report• Scios submits interim report to the Food and Drug

Administration on NATRECOR® (nesiritide)• January 3, 2006• Scios Inc today announced it is submitting an interim

report to the U.S. Food and Drug Administration…

• The interim report contains two additional deaths that had occurred within 30 days after treatment with NATRECOR but had not been initially reported to the company.

Aaronson KD, et al. JAMA. 2006;296:1465–1466.

Mortality within 30 Days of TreatmentAssociated with Nesiritide or Control Therapy

The Real Chuck?